The ubiquitin-proteasome system is the major pathway for intracellular protein degradation in eukaryotes. Substrates of this pathway acquire a covalently linked polyubiquitin chain through the action of a cascade of ubiquitin activating and conjugating enzymes. This ubiquitin chain serves as the recognition motif for a large multi-subunit protease known as the proteasome, which processively degrades the substrate into small polypeptides while releasing ubiquitin for reuse (Pickart and Cohen. (2004). Proteasomes and their kin: proteases in the machine age. Nat. Rev. Mol. Cell. Biol. 5, 177-187).